The present studies have further characterized the natural killer (NK) cell system in rats. Results using a wide variety of target cells have shown that the naturally cytotoxic effector cells for both normal bone marrow and tumor targets are all included in the large granular lymphocyte (LGL) subpopulation; further emphasizing the importance of these cells in controlling bone marrow growth and differentiation and in antitumor immune surveillance. Studies with transplantable LGL leukemias in F344 rats have demonstrated a great deal of morphological and functional similarity with normal LGL. Similarities were also noted between these LGL tumors and some previously reported cases of human TGamma-CLL. Biochemical analysis of these rat LGL leukemias has resulted in the purification of cytoplasmic granules containing highly cytolytically active material(s). Rabbit antibodies against these granules block both rat and human NK and antibody-dependent cellular cytotoxicity (ADCC). The present studies demonstrate that a granule component(s) is necessary for the lytic activity of LGL in both NK and ADCC, and provide the first direct evidence that a secretory event involving these granules is part of the lytic process.